Tag Archives: tocilizumab

Tumor necrosis factor inhibitor drugs began to dominate treatment of inflammatory diseases like rheumatoid arthritis, psoriasis, and the inflammatory bowel diseases ulcerative colitis and Crohn’s disease a little over a decade again. Now, the time when the importance of the anti-TNFs will wane and newer drugs will take their place is clearly visible on the horizon. It hasn’t happened yet, but the era of anti-TNF dominance for treating inflammatory diseases that persisted throughout the 2000s will end in the next 5 years.

The anti-TNF era began in 1998 with the approval of etanercept (Enbrel) for rheumatoid arthritis and infliximab (Remicade) to treat Crohn’s disease. In subsequent years, the list of approved anti-TNFs expanded to include adalimumab (Humira), golimumab (Simponi), and certolizumab (Cimzia), and the approved indications grew to include many inflammatory disease of joints, the GI tract, and skin. The anti-TNFs revolutionized inflammatory disease treatment and made treatment to remission possible for many patients.

But reports from just the past month show that new agents are overtaking the anti-TNFs.

In May, I reported from Digestive Disease Week on phase III trial results with vedolizumab, which was compared against placebo for patients with ulcerative colitis. One of the study investigators noted that vedolizumab beat the placebo arm for steroid-free clinical remission by 30 percentage points. “Nothing else is that good,” Dr. William Sandborn, professor of medicine and chief of gastroenterology at the University of California, San Diego, told me, and the benchmark he had in mind was the performance of the anti-TNFs in similar patients.

More recently, at the European Congress of Rheumatology earlier this month I heard a report on a head-to-head comparison of the anti-IL-6 drug tocilizumab (Actemra) and the anti-TNF adalimumab in patients with rheumatoid arthritis. After 24 weeks of monotherapy, patients on tocilizumab had nearly a fourfold higher remission rate than patients on adalimumab. Though the monotherapy trial design did not mimic the way most rheumatoid arthritis patients get treated, the new drug tocilizumab absolutely blew adalimumab out of the water in a rare head-to-head comparison among different classes of anti-inflammatory drugs.

And at the same meeting several talks highlighted another new anti-inflammatory class of agents coming soon to the U.S. market, the Janus kinase (JAK) inhibitors, such as tofacitinib, which is expected to received FDA approval later this summer. Phase III results show that tofacitinib has safety and efficacy that seems at least comparable to anti-TNF drugs, with the advantage of oral dosing.

Vedolizumab, tocilizumab, and tofacitinib are just the tip of new waves of anti-inflammatory drugs that will soon substantially alter a landscape that the anti-TNFs have mostly had to themselves for the past 14 years. For the moment, the anti-TNFs have the advantage of a longer track record for safety, but changing that is only a matter of time.

Well, it’s that time of year: A time for reflection, a time for too much fattening food and drink, and probably way too much togetherness with relatives you spend the rest of the year trying to avoid. Here at Notes From the Road, we’d like to take a moment to reflect on the bounty that medicine has provided us in 2010 by sharing our most-viewed posts, as nearest as we can determine.

The Juvenile Diabetes Research Foundation’s announcement yesterday of a partnership with Animas Corp. and DexCom Inc. to develop a first-generation automated insulin delivery system brought to my mind a question that is often debated in diabetes circles: Would a fully automated “artificial pancreas” represent a “cure” for type 1 diabetes? (Read more.)

There’s a fascinating study in today’s Journal of the American Medical Association. It’s a meta-analysis of randomized controlled trials comparing antidepressants vs. placebo. And it showed that the placebo effect is so strong in depression that placebos work as well as paroxetine (Paxil) and imipramine (Tofranil) for all patients except those with major depressive disorder that’s classified as “very severe.” Placebo tied active medication for “mild,” “moderate,” and even “severe” depression. (Read more.)

One year after asking the Roche group to submit additional data for its monoclonal antibody tocilizumab, the FDA has approved the biologic agent for the treatment of moderate to severe rheumatoid arthritis. (Read more.)

Like many of the neurologists attending the annual meeting of the American Headache Society, I slipped into the hotel lobby during breaks in the program to watch World Cup soccer in bits and pieces. The images of players heading the ball caught my eye in a new way after hearing a couple of presentations about the associations between head injuries and persistent, more frequent, and disabling headaches. (Read more.)

The American Diabetes Association’s decision earlier this month to officially endorse hemoglobin A1c as a diagnostic test for diabetes is either timely, inappropriate, or long overdue, depending on whom you talk to. (Read more.)

Rheumatologists have remade rheumatoid arthritis, a pretty big deal for them if only because it’s “the major systemic rheumatic disease that we as a specialty treat,” said Dr. Michael E. Weinblatt, a Harvard rheumatologist, at the end of a 90-minute session on Sunday afternoon that unveiled a new definition of rheumatoid arthritis to the world. (Read more.)

Next week more than 40,000 people from around the world will migrate to Black Rock Desert in Nevada to create a week-long community where clothing is optional, illicit drugs are common, and fantastical artwork is everywhere. Dr. Marc Nelson will be one of them at an event called Burning Man. (Read more.)

Any growing tolerance of a person’s right to his or her own sexuality that is evidenced in the mainstream culture has yet to impact the Lord of the Flies scenarios that exist for gay, lesbian, bisexual, transgendered, or questioning students in many schools across the country—something that is comically but bitingly portrayed in the Fox hit series “Glee.” (Read more.)

Thanks for following us in 2010. We hope you’ll be back for more in 2011.

Targeted treatment can be wonderful, producing dramatically effective patient improvement with little or no adverse effects.

One apparent, new example of a highly targeted, remarkably effective treatment reported last month at the annual European Congress of Rheumatology (EULAR) came from a study of 112 children and adolescents with systemic juvenile idiopathic arthritis (JIA) randomized to treatment with the interleukin (IL)-6 inhibitor tocilizumab or placebo.

image courtesy Flickr user Living Juicy

After 12 weeks of treatment, the 75 patients randomized to a tocilizumab infusion every 2 weeks had a 85% ACR50 response rate, a 71% ACR70 response rate, and even a 37% ACR90 response rate, compared with respective response rates of 11%, 8%, and 5% among 37 patients randomized to placebo treatment in a multicenter study. These responses occurred with just three of the 75 patients on tocilizumab having a serious adverse event.

An ACR70 response rate of 71% is spectacular, especially compared with a matched placebo rate of 8% and after just 12 weeks of treatment. An ACR70 response means that the patient had a 70% reduction in swollen and tender joints as well as in at least three of five other response categories, and is at the upper end of response levels usually measured in arthritis trials. (Some studies only look at ACR20 responses, patients having a 20% improvement in their joint counts and other symptoms.)

By comparison, in one of the phase III trials that led to tocilizumab’s approval as a treatment for rheumatoid arthritis earlier this year, the TOWARD trial with more than 1,200 rheumatoid arthritis patients, the ACR70 response rate after 24 weeks of treatment was 21% in the tocilizumab recipients and 3% in the placebo group.

Why did tocilizumab do so well for systemic JIA? “A vast body of evidence suggests that IL-6 drives” the disease, said Dr. Fabrizio De Benedetti, the Italian rheumatologist who led the new study.

Apply the right drug to the right patients, and the results can be incredibly successful. The only problem is that systemic JIA is not very common. It constitutes about 10%-15% of all JIA, itself a relatively uncommon disorder. Dr. De Benedetti estimated that perhaps about 3,000 patients with systemic JIA exist throughout the entire European Union, a population of about 500 million.

One year after asking the Roche group to submit additional data for its monoclonal antibody tocilizumab, the FDA has approved the biologic agent for the treatment of moderate to severe rheumatoid arthritis (see story).

Although the drug, to be marketed under the name Actemra, is entering a somewhat crowded biologics market—it is joining abatacept, adalimumab, anakinra, etanercept, infliximab, and rituximab —it is the first and so far only interleukin-6 (IL-6) receptor inhibitor to be approved for the indication, and clinicians are cautiously optimistic that it will improve the lives of patients who have not responded to therapy with methotrexate alone or in combination with other disease modifying antirheumatic drugs (DMARDS).

In fact, tocilizumab has been approved specifically for those adult patients who have failed methotrexate and one or more tumor necrosis factor antagonist, according to an announcement released today by the drug’s manufacturer, Roche Holding AG.

The FDA approval is a much-anticipated development, according to Dr. Larry Greenbaum, a rheumatologist in private practice in Indianapolis. “It’s very exciting. Actually, one of the drug representatives has been stopping by my office for the last year or two, dropping hints about this product, although the company has not been allowed to “detail” the drug before release. And of course, there have been many drug company ads creating a crescendo of drum beats before the official release date,” he said in an interview.

The novelty of tocilizumab lends to the excitement. “There are multiple anti-TNF medications currently, and the reps for those drugs are trying very hard to convince clinicians to choose one medication over another, even though they are probably more similar than different,” Dr. Greenbaum commented. As an IL-6 blocker, tocilizumab IS different, which is why the industry is buzzing, he noted.

The new-drug hype notwithstanding, there are still a number of questions to be answered before clinicians can consider the potential clinical impact of tocilizumab, according to Dr. Greenbaum. “The main questions for me are: Is this medication any safer or more dangerous than the current biologic drugs? Is this medication more or less affordable (or accessible) than the current biologics? Where does this medication belong in the treatment algorithm?

“Undoubtedly, the company is going to try and convince doctors to use this medication immediately after methotrexate failure, but they will first have to convince doctors (and insurers) that this strategy is warranted,” Dr. Greenbaum said.

Of particular concern are the side effects. Biologic agents are powerhouse drugs, and powerhouse drugs often have the potential for causing serious adverse effects. Among the serious tocilizumab-related adverse events that have been reported in pivotal clinical trials include infections that lead to hospitalization or death, including tuberculosis, bacterial, invasive fungal, viral and other infections; gastrointestinal perforations; hypersensitivity reactions; and cellulitis. In March 2009, Roche’s Chugai Pharmaceuticals reported that among nearly 5,000 rheumatoid arthritis patients in Japan who had been treated with tocilizumab between April 2008 and February 2009, 15 deaths occurred and the possibility of a link to the drug could not be denied, although the exact causes of the deaths were unknown, according to a press release issued by the company.

Some of the common side effects associated with tocilizumab include upper respiratory infections, including pneumonia, inflammation of the nose and throat, headache, high blood pressure, increased liver enzymes, increased cholesterol levels, neutrophil decreases, and platelet decreases, according to the company.

The drug’s approval comes with a Risk Evaluation and Mitigation Strategy (REMS), which includes a medication guide, communication plan, and timetable for submission of assessments. The drug itself will be available the week of January 18, 2010.

The annual meeting of the American College of Rheumatology, San Francisco

Here at the annual meeting of the American College of Rheumatology, the talk between investigators is about how the Food and Drug Administration has stopped approving new drugs. This case of regulatory paralysis makes no sense, according to people who talked to me on the subject. FDA advisory panels have recommended approval of drugs like febuxostat for gout and tocilizumab for rheumatoid arthritis. Rheumatologists are not by nature a cynical bunch but no one I spoke with expected either of these agents to be approved in 2008. Why?

Like everything in rheumatology, the answer seems to be multifactorial. The FDA has been diagnosed here with a case of post-Vioxx PTSD. The agency seems terrified of making a mistake of that magnitude again. The other factor is more practical: FDA is awaiting the results of the presidential election, with its attendant new administration and eventual appointment of a fresh FDA commissioner.

The exhibit floor is jammed with booths, some large to promote approved agents and others describing agents that are hanging fire in the approval process. I felt relieved by the sight of products that do not require FDA approval-such as equipment for office–based ultrasound, fluoroscope of small joints, and DXA scans. My favorite booth promoted the large handled kitchen products of OXO. How clever to market these thick gripped peelers and ergonomically responsible lettuce spinners (priced rather steeply as all fans of Williams and Sonoma know) to rheumatologists and physical and occupational therapists who will in turn recommend them to patients whose hand pain makes it difficult to grip smaller kitchen tools. And who is to say that the pain relief offered by these thoughtfully designed gadgets does not make a significant improvement in the quality of life of patients with rheumatic diseases of the small joints?